Journal Article
. 2009 Jul; 15(25):3134-41.
doi: 10.3748/wjg.15.3134.

Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease

Carsten Gnewuch 1 Gerhard Liebisch  Thomas Langmann  Benjamin Dieplinger  Thomas Mueller  Meinhard Haltmayer  Hans Dieplinger  Alexandra Zahn  Wolfgang Stremmel  Gerhard Rogler  Gerd Schmitz  
  • PMID: 19575493
  •     48 References
  •     22 citations


Aim: To determine free and conjugated serum bile acid (BA) levels in inflammatory bowel disease (IBD) subgroups with defined clinical manifestations.

Methods: Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy controls by liquid chromatography coupled to electrospray ionization tandem mass spectrometry.

Results: Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the secondary BA lithocholic acid (LCA), was increased significantly in Crohn's disease (CD) and ulcerative colitis (UC), while most other serum BA species were decreased significantly. Total BA, total BA conjugate, and total BA glycoconjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as significantly increased as the secondary BAs LCA, ursodeoxycholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenodeoxycholic acid, were increased significantly compared to controls and patients without surgical interventions.

Conclusion: Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diagnostic characterization and differentiation of IBD subgroups with defined clinical manifestations.

Bile acid studies in patients with Crohn's colitis.
P Rutgeerts, Y Ghoos, G Vantrappen.
Gut, 1979 Dec 01; 20(12). PMID: 527881    Free PMC article.
Pharmacology of ursodeoxycholic acid, an enterohepatic drug.
A F Hofmann.
Scand J Gastroenterol Suppl, 1994 Jan 01; 204. PMID: 7824870
Altered fecal bile acid pattern in patients with inflammatory bowel disease.
W Kruis, H D Kalek, F Stellaard, G Paumgartner.
Digestion, 1986 Jan 01; 35(4). PMID: 3817328
Update in inflammatory bowel disease pathogenesis.
Gerhard Rogler.
Curr Opin Gastroenterol, 2005 Feb 11; 20(4). PMID: 15703658
Hepatobiliary manifestations of inflammatory bowel disease.
V Raj, D R Lichtenstein.
Gastroenterol Clin North Am, 1999 Jun 18; 28(2). PMID: 10372279
Role of genes, the environment and their interactions in the etiology of inflammatory bowel diseases.
Farid E Ahmed.
Expert Rev Mol Diagn, 2006 May 19; 6(3). PMID: 16706738
How bile acids confer gut mucosal protection against bacteria.
Alan F Hofmann, Lars Eckmann.
Proc Natl Acad Sci U S A, 2006 Mar 16; 103(12). PMID: 16537368    Free PMC article.
Disturbances of bile acid metabolism in intestinal disease.
K W Heaton.
Clin Gastroenterol, 1977 Jan 01; 6(1). PMID: 330053
Hepatotoxic effect of bile acids in inflammatory bowel disease.
M J Dew, G P van Berge Henegouwen, A W Huybregts, R N Allan.
Gastroenterology, 1980 Jun 01; 78(6). PMID: 7372059
Nuclear receptors as targets for drug development: regulation of cholesterol and bile acid metabolism by nuclear receptors.
Makoto Makishima.
J Pharmacol Sci, 2005 Feb 24; 97(2). PMID: 15725701
Postprandial serum bile acids in resected and non-resected patients with Crohn's disease.
R Heuman, R Sjödahl, P Tobiasson, C Tagesson.
Scand J Gastroenterol, 1982 Jan 01; 17(1). PMID: 7134829
Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease?
James L Boyer.
Gastroenterology, 2005 Aug 09; 129(2). PMID: 16083726
Loss of detoxification in inflammatory bowel disease.
Thomas Langmann, Gerd Schmitz.
Nat Clin Pract Gastroenterol Hepatol, 2006 Jul 05; 3(7). PMID: 16819479
Bile acid metabolism in patients with Crohn's disease in terminal ileum.
L Tougaard, B Giese, B H Pedersen, V Binder.
Scand J Gastroenterol, 1986 Jun 01; 21(5). PMID: 3749801
Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.
Takeshi Inagaki, Antonio Moschetta, +9 authors, Steven A Kliewer.
Proc Natl Acad Sci U S A, 2006 Feb 14; 103(10). PMID: 16473946    Free PMC article.
Highly Cited.
Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes.
Thomas Langmann, Christoph Moehle, +5 authors, Gerd Schmitz.
Gastroenterology, 2004 Jul 06; 127(1). PMID: 15236169
Extraintestinal manifestations in inflammatory bowel disease.
Silvio Danese, Stefano Semeraro, +5 authors, Antonio Gasbarrini.
World J Gastroenterol, 2006 Jan 27; 11(46). PMID: 16437620    Free PMC article.
Primary sclerosing cholangitis.
A Jorge, J Findor, C Esley, E Bruch.
Z Gastroenterol, 1988 Jun 01; 26(6). PMID: 3206917
Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism.
Jyrki J Eloranta, Gerd A Kullak-Ublick.
Arch Biochem Biophys, 2004 Dec 08; 433(2). PMID: 15581596
Etiology and pathogenesis of inflammatory bowel disease.
C Schmidt, A Stallmach.
Minerva Gastroenterol Dietol, 2005 Jul 02; 51(2). PMID: 15990703
Fasting and postprandial serum concentrations of glycine- and taurine-conjugated bile acids in Crohn's disease.
K Linnet, A Mertz Nielsen.
Scand J Gastroenterol, 1983 May 01; 18(3). PMID: 6673068
New concepts in the pathophysiology of inflammatory bowel disease.
Giorgos Bamias, Mark R Nyce, +3 authors, American Physiological Society.
Ann Intern Med, 2005 Dec 21; 143(12). PMID: 16365470
New developments in aetiological mechanisms of inflammatory bowel disease.
Jürgen Schölmerich.
Eur J Gastroenterol Hepatol, 2003 Jul 04; 15(6). PMID: 12840666
Decreased absorption of ingested unconjugated chenodeoxycholic acid in patients with Crohn's disease.
R Heuman, R Sjödahl, P Tobiasson, C Tagesson.
Scand J Gastroenterol, 1983 Jan 01; 18(1). PMID: 6675175
Role of ABCG1 and other ABCG family members in lipid metabolism.
G Schmitz, T Langmann, S Heimerl.
J Lipid Res, 2001 Oct 09; 42(10). PMID: 11590207
Bile salt biotransformations by human intestinal bacteria.
Jason M Ridlon, Dae-Joong Kang, Phillip B Hylemon.
J Lipid Res, 2005 Nov 22; 47(2). PMID: 16299351
Highly Cited. Review.
Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease.
Gustav Paumgartner, Ulrich Beuers.
Clin Liver Dis, 2004 Apr 06; 8(1). PMID: 15062194
The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.
Steven A Kliewer, Bryan Goodwin, Timothy M Willson.
Endocr Rev, 2002 Oct 10; 23(5). PMID: 12372848
Highly Cited. Review.
Enterohepatic bile salt transporters in normal physiology and liver disease.
Gerd A Kullak-Ublick, Bruno Stieger, Peter J Meier.
Gastroenterology, 2003 Dec 31; 126(1). PMID: 14699511
Highly Cited. Review.
Serum bile acids in relation to disease activity and intake of dietary fibers in juvenile ulcerative colitis.
J Ejderhamn, B Strandvik.
Digestion, 1991 Jan 01; 50(3-4). PMID: 1667392
Serum-bile-acids in inflammatory bowel disease.
A A Mihas, R G Gibson, N Levy, B I Hirschowitz.
Lancet, 1977 Aug 20; 2(8034). PMID: 70618
[Lipids and total bile acids in the blood of patients with inflammatory bowel diseases].
N Kostić, M Bozanić, R Cvetković, A Adamov.
Srp Arh Celok Lek, 1990 Jan 01; 118(1-2). PMID: 2218731
Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis.
Ulrich Beuers.
Nat Clin Pract Gastroenterol Hepatol, 2006 Jun 03; 3(6). PMID: 16741551
Serum bile acids after a test meal in Crohn's disease.
K Samuelson, C Johansson, A Norman.
Scand J Clin Lab Invest, 1979 Oct 01; 39(6). PMID: 531481
Biotransformation of monoterpenes, bile acids, and other isoprenoids in anaerobic ecosystems.
P B Hylemon, J Harder.
FEMS Microbiol Rev, 1999 Feb 17; 22(5). PMID: 9990726
Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.
Gustav Paumgartner, Ulrich Beuers.
Hepatology, 2002 Aug 29; 36(3). PMID: 12198643
Highly Cited. Review.
Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray tandem mass spectrometry: a simple and rapid one-step method.
Debora Tagliacozzi, Alessia F Mozzi, +5 authors, Giorgio Federici.
Clin Chem Lab Med, 2004 Jan 08; 41(12). PMID: 14708888
Gallbladder bile composition in patients with Crohn 's disease.
Annika Lapidus, Jan-Erik Akerlund, Curt Einarsson.
World J Gastroenterol, 2006 Jan 28; 12(1). PMID: 16440420    Free PMC article.
Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms.
John Y L Chiang.
J Hepatol, 2004 May 05; 40(3). PMID: 15123373
Bile acid metabolism and vitamin B12 absorption in ulcerative colitis.
K Lenz.
Scand J Gastroenterol, 1976 Jan 01; 11(8). PMID: 1006150
Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis.
Darrell S Pardi, Edward V Loftus, +2 authors, Keith D Lindor.
Gastroenterology, 2003 Apr 03; 124(4). PMID: 12671884
Highly Cited.
Evaluation of fasting serum bile acid concentration in patients with liver and gastrointestinal disorders.
K Samuelson, A Aly, C Johansson, A Norman.
Scand J Gastroenterol, 1981 Jan 01; 16(2). PMID: 7313533
Induction of PXR-mediated metabolism by beta-carotene.
Ralph Rühl.
Biochim Biophys Acta, 2005 Jun 14; 1740(2). PMID: 15949683
The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts.
Sander M Houten, Johan Auwerx.
Ann Med, 2004 Oct 30; 36(7). PMID: 15513299
Bile acid regulation of hepatic physiology: III. Bile acids and nuclear receptors.
John Y L Chiang.
Am J Physiol Gastrointest Liver Physiol, 2003 Feb 11; 284(3). PMID: 12576301
Kinetics of primary bile acids in patients with non-operated Crohn's disease.
P Rutgeerts, Y Ghoos, G Vantrappen.
Eur J Clin Invest, 1982 Apr 01; 12(2). PMID: 6807684
Role of FXR in regulating bile acid homeostasis and relevance for human diseases.
Giovanni Rizzo, Barbara Renga, +2 authors, Stefano Fiorucci.
Curr Drug Targets Immune Endocr Metabol Disord, 2005 Sep 24; 5(3). PMID: 16178789
The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis.
J M Wolf, L A Rybicki, B A Lashner.
Aliment Pharmacol Ther, 2005 Oct 18; 22(9). PMID: 16225486
Profile of serum bile acids in noncholestatic volunteers: gender-related differences in response to fenofibrate.
J Trottier, P Caron, R J Straka, O Barbier.
Clin Pharmacol Ther, 2011 Jul 01; 90(2). PMID: 21716269    Free PMC article.
Epithelial markers of colorectal carcinogenesis in ulcerative colitis and primary sclerosing cholangitis.
Pavel Wohl, Tomas Hucl, +9 authors, Milos Kucera.
World J Gastroenterol, 2013 Apr 20; 19(14). PMID: 23599650    Free PMC article.
PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis.
Xueyan Zhou, Lijuan Cao, +9 authors, Haiping Hao.
Nat Commun, 2014 Sep 04; 5. PMID: 25183423    Free PMC article.
Chlorpromazine-induced perturbations of bile acids and free fatty acids in cholestatic liver injury prevented by the Chinese herbal compound Yin-Chen-Hao-Tang.
Qiaoling Yang, Fan Yang, +5 authors, Li Yang.
BMC Complement Altern Med, 2015 Apr 19; 15. PMID: 25887351    Free PMC article.
Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes.
Anna-Kathrin Schupp, Mirko Trilling, +7 authors, Dirk Graf.
J Virol, 2016 May 14; 90(15). PMID: 27170759    Free PMC article.
Interaction of gut microbiota with bile acid metabolism and its influence on disease states.
Christopher Staley, Alexa R Weingarden, Alexander Khoruts, Michael J Sadowsky.
Appl Microbiol Biotechnol, 2016 Nov 27; 101(1). PMID: 27888332    Free PMC article.
Highly Cited. Review.
HuangQin Decoction Attenuates CPT-11-Induced Gastrointestinal Toxicity by Regulating Bile Acids Metabolism Homeostasis.
Xu Wang, Dong-Ni Cui, +4 authors, Feng-Guo Xu.
Front Pharmacol, 2017 Apr 21; 8. PMID: 28424615    Free PMC article.
Urinary metabolic insights into host-gut microbial interactions in healthy and IBD children.
Francois-Pierre Martin, Ming-Ming Su, +5 authors, Andreas Nydegger.
World J Gastroenterol, 2017 Jun 15; 23(20). PMID: 28611517    Free PMC article.
Activin in acute pancreatitis: Potential risk-stratifying marker and novel therapeutic target.
Jonas J Staudacher, Cemal Yazici, +11 authors, Barbara Jung.
Sci Rep, 2017 Oct 08; 7(1). PMID: 28986573    Free PMC article.
High prevalence of cholestasis, with increased conjugated bile acids in inflammatory bowel diseases patients.
Marc Girardin, Antoine Hadengue, Jean-Louis Frossard, Swiss IBD Cohort Study Group.
World J Clin Cases, 2018 Apr 20; 6(4). PMID: 29670889    Free PMC article.
Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling.
Elizabeth A Scoville, Margaret M Allaman, +10 authors, Lori A Coburn.
Metabolomics, 2018 Apr 24; 14(1). PMID: 29681789    Free PMC article.
Role of bile acids in inflammatory bowel disease.
Elisa Tiratterra, Placido Franco, +3 authors, Giulia Roda.
Ann Gastroenterol, 2018 May 04; 31(3). PMID: 29720851    Free PMC article.
Attenuation of bile acid-mediated FXR and PXR activation in patients with Crohn's disease.
Aze Wilson, Ahmed Almousa, Wendy A Teft, Richard B Kim.
Sci Rep, 2020 Feb 07; 10(1). PMID: 32024859    Free PMC article.
Evaluating the structural complexity of isomeric bile acids with ion mobility spectrometry.
Xueyun Zheng, Francesca B Smith, +4 authors, Erin S Baker.
Anal Bioanal Chem, 2019 May 18; 411(19). PMID: 31098744    Free PMC article.
Serum Bile Acids Profiling in Inflammatory Bowel Disease Patients Treated with Anti-TNFs.
Giulia Roda, Emanuele Porru, +6 authors, Aldo Roda.
Cells, 2019 Aug 07; 8(8). PMID: 31382518    Free PMC article.
An Inverse Correlation of Serum Fibroblast Growth Factor 19 with Abdominal Pain and Inflammatory Markers in Patients with Ulcerative Colitis.
Magdalena Panek-Jeziorna, Agata Mulak.
Gastroenterol Res Pract, 2020 Jun 23; 2020. PMID: 32565779    Free PMC article.
Temporal Regulation of the Bacterial Metabolite Deoxycholate during Colonic Repair Is Critical for Crypt Regeneration.
Umang Jain, Chin-Wen Lai, +9 authors, Thaddeus S Stappenbeck.
Cell Host Microbe, 2018 Aug 21; 24(3). PMID: 30122655    Free PMC article.
Drug-induced cholestasis assay in primary hepatocytes.
Pieter Van Brantegem, Sagnik Chatterjee, +2 authors, Neel Deferm.
MethodsX, 2020 Oct 23; 7. PMID: 33088729    Free PMC article.
Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy.
Teresa Płatek, Evelyn Orso, +9 authors, Aldona Dembińska-Kieć.
Medicine (Baltimore), 2018 Dec 14; 97(49). PMID: 30544401    Free PMC article.
Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes.
Petar D Petrov, Leonor Fernández-Murga, +4 authors, Ramiro Jover.
Arch Toxicol, 2020 Jan 03; 94(2). PMID: 31894354
S-Propargyl-Cysteine Remodels the Gut Microbiota to Alleviate Rheumatoid Arthritis by Regulating Bile Acid Metabolism.
Zhou Wang, Yue Yu, +4 authors, Yi Zhun Zhu.
Front Cell Infect Microbiol, 2021 Aug 24; 11. PMID: 34422677    Free PMC article.
Bile Acids, Their Receptors, and the Gut Microbiota.
James C Poland, C Robb Flynn.
Physiology (Bethesda), 2021 Jun 24; 36(4). PMID: 34159805    Free PMC article.